To date, we know more than 1000 structural changes in the COL1A1 gene. Structural mutations in this gene account for about 45% and the remaining number of mutations are accounted for by other variants (nonsense mutations, reading frame shift mutations, splicing site mutations, deletions of the entire gene). According to literature data, the percent of new pathogenic mutations in two type I collagen genes (COL1A1/COL1A2) in Ukrainians with OI was 42.85%, in Chinese - 40.98%, in Swedes - 31.53% [ 4 , 12 , 19 ]. In the Chinese population, structural changes account for 54%, and haploinsufficiency mutations account for 46% [12], in the Ukrainian population the ratio is exactly 49% / 51% [ 19 ], which differs from our results. In population from Republic of Baskortostan structural mutations account for 41%, and haploinsufficiency mutations-59%.

The studies of the three-spiral peptide have shown that a simple replacement of glycine in the medium (Gly-Pro-Hyp) strongly destabilizes the chain and affects the clinical severity of Osteogenesis Imperfecta. We also determined that the degree of destabilization of the peptide depends on that which amino acid replaces glycine (Gly). The order of stability loss from the smallest to the largest is as follows: Ala ≤ Ser <Cys <Arg <val <Glu ≤ Asp [ 27 , 28 ]. Substitutions of glycine with alanine and serine have the least effect on the conformation and stability of the peptide and lead to a lighter course of the disease [ 28 ]. Furthermore, the degree of destabilization depends on the location of the mutation site [ 29 ].

In lethal types of OI glycine substitutions for Val, Asp, Glu and Arg are observed more often. On the contrary, glycine substitutions for serine and cysteine are rare in patients with fatal cases of OI [ 5 , 30 , 31 ].

According to the literature data, Gly residues are most often replaced by Ser or Cys [ 28 ].

Mutations c.358C>T, c.658C>T, c.1243C>T, c.2869C>T, c. 3076C>T, c.858+1G>A, c.1354-12G>A, c.3208-1G>C were detected in patients with type I of OI. Patients from other populations had similar clinical manifestations to patients from our study. Mutations c.1081C>T, c.2461G>A and c.2569G>T found in COL1A1 gene lead to severe clinical symptoms in our patients with the type III of OI than in patients from literature who had type I of OI [ 6 ].

Thus, the replacement of cytosine with thymine in the 1081 position of cDNA, leading to a stop codon in the proband from the Republic of Bashkortostan, led to severe clinical manifestations of the disease with type III of OI. He had multiple fractures, which led to deformities of the limbs and disability. The father with the same mutation had type I of OI. This change has been described 11 times, and the authors report a mild course of the disease with type I of OI [4,12,32,33,34,35]. The c.2461G>A mutation was registered in the database 31 times and described in patients with types I, II, III, and IV of OI [4,5,12,13,14,17,36,37,38,39,40,41]. Kloen and co-authors described in detail a patient with this mutation who had multiple fractures with poor healing as a result of this progressive deformation of the lower and upper extremities and compression fractures of the spine. The patient could not move independently [40]. The patient also has multiple fractures and deformities of the limbs, which correlates with type III of OI.

The c.2569G>T mutation in the COL1A1 gene was described 8 times [5,42]. The phenotypes of patients also differed (II, III, IV types of OI). In the patient, this change led to type III of OI. The patient had multiple fractures, short stature, and deformities of the bone system.

There are about 600 mutations described in the COL1A2 gene. According to the international database on osteogenesis imperfecta, the vast majority of mutations in the COL1A2 gene are missense mutations, which account for approximately 74% [6].

It is noted that the most frequent structural defects of type I collagen causing osteogenesis imperfecta are glycine substitutions in the spiral domain. Glycine substitutions delay helical folding, increasing the access time for enzyme modification. Thus, in sample of OI patients, the most frequent missense mutations were glycine substitutions, which accounted for 73% of all structural changes identified in collagen genes.

Mutations in different type I collagen chains differ in their phenotypic effect. In the α1 chain of collagen type I, substitutions with charged or branched side chains disrupt the stability of the spiral and are predominantly lethal. Substitutions in the two main ligand-binding regions near the carboxyl end of the α1 chain have exceptionally lethal outcomes, indicating important interactions between the collagen monomer and non-collagen matrix proteins. In the α2 chain of type I collagen, substitutions are mostly non-lethal; however, eight lethal clusters along the chain align with proteoglycan binding sites on collagen fibrils. Finally, less than 5% of the mutations causing classical osteogenesis imperfecta occur in the procollagen C-propeptide, disrupting chain association or folding [43].

The c.874G>A mutation detected in the COL1A2 gene was published 6 times [4,20,41] and resulted in type I in 5 patients from Sweden and Germany [4,20] as well as a patient from Belarus. However, Duy described that this change led to type III of OI in a patient from Vietnam [41].

The c.2756G>A mutation of the COL1A2 gene was previously published in a patient with intrauterine fractures and various anomalies with type II of OI [44]. The patient had short stature, blue sclera, and multiple fractures, which led to disability of the patient and progressive deformities of the lower extremities with type III of OI.

The c.3034G>A mutation has been published 26 times in the database on OI [4,5,38,39,41,43,45,46,47]. Patients with this change had III and IV types of OI. According to clinical signs, our patient was classified as type III of OI with blue sclera and multiple deforming fractures.

According to literature data, haploinsufficiency mutations in COL1A1/COL1A2 genes resulting from splicing site mutations, meaningless mutations, deletions, or insertions usually create a premature termination codon. These aberrant RNAs are usually decomposed by nonsense-mediated mRNA decay (NMD). With normal type I collagen α chains produced by the wild-type allele, haploinsufficiency usually leads to a moderate OI phenotype [5]. On the other hand, the dominant negative effects are the result of missense mutations or mutations of the premature terminating codon, which avoid nonsense-mediated mRNA decay. Binding of the mutated α chain with normal α chains produced by the wild-type allele leads to an abnormal type of collagen I. Classically known OI mutations with a dominant negative effect represent the substitution of an amino acid for one of the mandatory glycine residues. They are found in every third position in the COL1A1 chain and other mutations, such as defects in the passage of exons or deletions in the reading frame. Most cases of OI with dominant negative effects are usually more serious than cases of haploinsufficiency [48].

It hopes that the mutations in patients with OI and the clinical characteristics that has been described will contribute to the understanding of genotypic–phenotypic correlations.

The phenotype of our patient is similar to the patients described by Baldridge et al. (2008), who noted that mutations in this gene lead to different clinical characteristics compared to patients with mutations in type I collagen genes [49]. Patients are characterized by white sclera, round face, and deformities of the lower extremities. As the researchers note, zero mutations in the P3H1 gene cause type III of OI and are severe or lethal and lead to excessive modification of the entire spiral region of collagen. The P3H1 enzyme itself causes 3-hydroxylation of α1(I) Pro986 in type I collagen as part of a complex of three proteins (P3H1, CRTAP, and CypB) in a ratio of 1:1:1. P3H1 is a catalytically active component, whereas CRTAP is an auxiliary protein without a catalytic domain. Prolyl-3-hydroxylation is one of several modifications of pro-chains that contribute to the proper stacking, stability, and secretion of procollagen. Prolyl-4-hydroxylation is important for the thermal stability of the triple helix, while lysine hydroxylation and hydroxylysine glycosylation contribute to the extracellular stability of cross-links between molecules [50]. Zero mutations of P3H1 actually cancel the 3-hydroxylation of type I collagen. The absence of hydroxylation of α1(I) Pro986 and/or the direct chaperone effect of P3H1 leads to a delay in the folding of the collagen spiral [51]. Patients with mutations in this gene have been described in African Americans, Africans, Pakistanis, and Arabs. The researchers note that mutations in this gene most often occurred in consanguineous patients. Pepin et al. 2013 described founder-effect mutations in the African population [49,51,52]. Zero mutations in P3H1 or CRTAP lead to the absence of both proteins in mutant cells because these proteins are mutually supportive in the complex and ultimately lead to similar clinical signs in patients with OI.

Type V of OI is unique among all types of osteogenesis imperfecta: most patients (approximately 95%) with type V have the same heterozygous mutation in IFITM5, a point mutation in 5′-UTR (c.-14C>T), which generates a new starting codon and adds five residues to the N–terminal end of the protein. Patients with this type have moderate bone dysplasia with a different combination of distinctive features, including ossification of the interosseous membrane of the forearm (76–100%) and dislocation of the radial head (36–88%) and its displacement (86%) [53]. More than half of patients with type V develop hyperplastic corns during fracture healing. The sclera hue varies, and the teeth remain normal. All patients with type V have a distinct mesh plate on bone histology [54,55, 56 , 57 , 58 ].